RO7656594 for Prostate Cancer
Recruiting in Palo Alto (17 mi)
+33 other locations
Age: 18+
Sex: Male
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Genentech, Inc.
Must be taking: AR-targeted therapy
Must not be taking: AR protein degrader
Disqualifiers: CNS metastases, Leptomeningeal disease, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial is testing a new drug called RO7656594 to see if it is safe and effective for people with advanced prostate cancer. The study focuses on patients whose cancer has spread and may not respond to current treatments. Researchers are looking at how the drug moves through the body and its impact on cancer cells to find the best dose and schedule for future studies.
Will I have to stop taking my current medications?
The trial requires that you stop taking any approved systemic anti-cancer therapy at least 14 days before starting the study treatment. If you're on an investigational agent, you need to stop it 28 days before. Other medications are not specifically mentioned, so it's best to discuss with the trial team.
What data supports the effectiveness of the drug RO7656594 for prostate cancer?
Research shows that targeting RORγ, which is involved in prostate cancer, can reduce tumor growth by blocking androgen receptor activity. This suggests that drugs like RO7656594, which may work similarly, could be effective in treating prostate cancer.
12345What is known about the safety of RO7656594 for prostate cancer treatment?
The research does not provide specific safety data for RO7656594, but similar treatments for prostate cancer, like novel oral anti-androgens, have been associated with increased fatigue and decreased risk of anemia. Patients should be monitored for these side effects.
14678What makes the drug RO7656594 unique for treating prostate cancer?
RO7656594 targets RORγ, a protein that drives androgen receptor (AR) hyperactivity in castration-resistant prostate cancer (CRPC). By blocking RORγ, this drug suppresses AR signaling and tumor growth, offering a novel approach compared to traditional therapies like androgen deprivation therapy, which often face resistance.
1691011Eligibility Criteria
This trial is for men with advanced or metastatic prostate cancer who have already tried at least one second-generation hormone therapy and a taxane chemotherapy, unless they can't tolerate or refused the chemo. They should be relatively active and able to care for themselves (ECOG ≤1).Inclusion Criteria
I am fully active and can carry on all pre-disease activities without restriction.
My prostate cancer has spread and is not small-cell or neuroendocrine type.
I have been treated with a specific prostate cancer medication before.
+1 more
Exclusion Criteria
I have brain metastases or leptomeningeal disease that hasn't been treated.
I haven't had cancer treatment in the last 14 days or within the drug's elimination period.
Treatment with any investigational agent within 28 days prior to the first study treatment
+1 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Participants receive RO7656594 at increasing doses in 28-day cycles until a threshold is reached
Varies per cohort
Multiple visits per cycle
Expansion
Participants receive RO7656594 at or below the maximum tolerated dose
Up to 12 months
Multiple visits per cycle
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study is testing RO7656594's safety, how it affects the body, and its effectiveness in treating prostate cancer. Participants will receive different doses of RO7656594 to find out what amount works best for future studies.
2Treatment groups
Experimental Treatment
Group I: Stage 2: ExpansionExperimental Treatment1 Intervention
Participants will receive RO7656594 at or below the maximum tolerated dose (MTD) or maximum administered dose (MAD).
Group II: Stage 1: Dose EscalationExperimental Treatment1 Intervention
Participants will receive RO7656594 administered at a specified dose on specific days in each 28-day cycle. The dose will be increased in successive cohorts until a study-specific threshold is reached.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Princess Margaret HospitalToronto, Canada
Sarah Cannon Research Institute / Tennessee OncologyNashville, TN
Yale Cancer CenterNew Haven, CT
SCRI Oncology PartnersNashville, TN
More Trial Locations
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Who Is Running the Clinical Trial?
Genentech, Inc.Lead Sponsor
References
New Therapeutic Target for Prostate Cancer. [2017]New research indicates a potential therapeutic target for castration-resistant prostate cancer: RORγ, which is abundant in the disease, can drive androgen receptor hyperactivity. Blocking RORγ with small-molecule antagonists suppresses AR and impedes tumor growth in mice bearing human prostate tumors, including a model resistant to the antiandrogen enzalutamide.
Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy. [2022]In SPARTAN, apalutamide improved metastasis-free and overall survival for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) with a prostate-specific antigen doubling time of ≤10 mo.
Deep Prostate-specific Antigen Response following Addition of Apalutamide to Ongoing Androgen Deprivation Therapy and Long-term Clinical Benefit in SPARTAN. [2022]Apalutamide plus androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS), overall survival (OS), and time to prostate-specific antigen (PSA) progression in the placebo-controlled SPARTAN study of high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC).
Safety and Antitumour Activity of ODM-201 (BAY-1841788) in Chemotherapy-naïve and CYP17 Inhibitor-naïve Patients: Follow-up from the ARADES and ARAFOR Trials. [2019]ODM-201, a new androgen receptor antagonist for treatment of metastatic castration-resistant prostate cancer (mCRPC), demonstrated antitumour activity and acceptable tolerability in phase 1/2 trials.
Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study. [2018]ODM-201 is a novel second-generation androgen receptor inhibitor for the treatment of metastatic castration-resistant prostate cancer (mCRPC).
Targeting Feedforward Loops Formed by Nuclear Receptor RORγ and Kinase PBK in mCRPC with Hyperactive AR Signaling. [2022]Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive disease with few therapeutic options. Hyperactive androgen receptor (AR) signaling plays a key role in CRPC progression. Previously, we identified RAR-related orphan receptor gamma (RORγ) as a novel key driver of AR gene overexpression and increased AR signaling. We report here that several RORγ antagonists/inverse agonists including XY018 and compound 31 were orally effective in potent inhibition of the growth of tumor models including patient-derived xenograft (PDX) tumors. RORγ controls the expression of multiple aggressive-tumor gene programs including those of epithelial-mesenchymal transition (EMT) and invasion. We found that PDZ binding kinase (PBK), a serine/threonine kinase, is a downstream target of RORγ that exerts the cellular effects. Alterations of RORγ expression or function significantly downregulated the mRNA and protein level of PBK. Our further analyses demonstrated that elevated PBK associates with and stabilizes RORγ and AR proteins, thus constituting novel, interlocked feed-forward loops in hyperactive AR and RORγ signaling. Indeed, dual inhibition of RORγ and PBK synergistically inhibited the expression and function of RORγ, AR, and AR-V7, and the growth and survival of CRPC cells. Therefore, our study provided a promising, new strategy for treatment of advanced forms of prostate cancer.
Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer. [2020]We report the design, optimization, and biological evaluation of nuclear receptor RORγ inverse agonists as therapeutic agents for prostate cancer treatment. The most potent compound 27 (designated as XY101) exhibited cellular activity with an IC50 value of 30 nM in a cell-based reporter gene assay with good selectivity against other nuclear receptor subtypes. The cocrystal structure of 27 in complex with the RORγ ligand binding domain provided a solid structural basis for its antagonistic mechanism. 27 potently inhibited cell growth, colony formation, and the expression of AR, AR-V7, and PSA. 27 also exhibited good metabolic stability and a pharmacokinetic profile with oral bioavailability of 59% and a half-life of 7.3 h. Notably, 27 demonstrated promising therapeutic effects with significant tumor growth inhibition in a prostate cancer xenograft model in mice. The potent, selective, metabolically stable, and orally available RORγ inverse agonists represent a new class of compounds as potential therapeutics against prostate cancer.
Risk of Fatigue and Anemia in Patients With Prostate Cancer Treated With Novel Oral Anti-androgens: A Meta-Analysis of Randomized Controlled Trials. [2022]Novel oral anti-androgens (NOAAs) represent a new class of drugs that are being approved for prostate cancer. However, fatigue and anemia are among the most common treatment-related symptoms. Hence, we conducted a meta-analysis of randomized controlled trials (RCTs) to investigate the relative risks (RRs) of fatigue and anemia associated with NOAAs. PubMed, Cochrane, EMBASE, and abstracts presented at the annual meeting of the American Society of Clinical Oncology and European Society of Clinical Oncology were searched for phase III and V RCTs of NOAAs from January 2000 to March 2020. Safety profile from each selected study was evaluated for all-grade and high-grade fatigue and anemia adverse events. The RRs with 95% confidence intervals (95% CIs) were calculated using random-effects for all-grade and high-grade events. Our analysis involved 15 RCTs, including 16,795 patients. Overall, 9,177 patients were treated with NOAAs in the experimental arm, whereas 7,095 received a standard of care in the control arm. The RR of all-grade and high-grade fatigue was 1.26 (95% CI 1.15-1.38) and 1.24 (95% CI 0.83-1.84), and that of all-grade and high-grade anemia was 0.81 (95% CI 0.77-1.19) and 0.81 (95% CI 0.61-1.06), respectively. Our findings suggest that NOAAs are associated with an increased risk of fatigue but decreased risk of anemia. Patients should be frequently monitored to identify adverse events to improve oncological outcomes and optimize the overall treatment efficacy and safety. Not all the RCTs addressed fatigue and anemia simultaneously as side effects of NOAA treatment.
ROR2 suppresses metastasis of prostate cancer via regulation of miR-199a-5p-PIAS3-AKT2 signaling axis. [2021]Bones are the most common metastatic sites for prostate cancer (PCa). Receptor tyrosine kinase-like orphan receptor 2 (ROR2), a noncanonical Wnt receptor, plays crucial roles in skeletal morphogenesis, osteoblast differentiation, and bone formation. The role of ROR2 in PCa metastasis is unclear. We analyzed online datasets from Oncomine as well as using IHC staining on tissue array to determine the relationship between ROR2 expression level and disease outcome of PCa. To investigate how ROR2 regulates migration and invasion of PCa cells, we performed transwell assay and orthotopic xenograft model in nude mice. We then applied the Micro-Western Array (MWA), a high-throughput western blotting platform to analyze the downstream signaling pathways being regulated by ROR2. Compared with nonmalignant PZ-HPV-7 and RWPE-1 cells, PCa cell lines express lower level of ROR2 protein. Constitutive expression of ROR2 in PC-3, DU-145, or C4-2B PCa cells significantly suppressed the cell migration, invasion, and epithelial-mesenchymal transition (EMT) proteins. MWA, western blotting, and microRNA analysis showed that elevation of ROR2 suppressed the expression of miR-199a-5p, which in turn increased the expression of PIAS3. The upregulation of PIAS3 then decreased AKT2 and the phosphorylation of AKT, resulting in the inhibition of migration and invasion of PCa cells both in vitro and in orthotopic xenograft mice model. IHC staining of tissue array and Oncomine datasets analysis indicated that the gene and protein level of ROR2 is much lower in metastatic prostate tumors as compared with primary tumors or adjacent normal prostate tissues. Low level of ROR2 correlated to poor survival and high recurrent frequency in PCa patients. In conclusion, we discovered that ROR2 suppresses PCa metastasis via regulation of PIAS3-PI3K-AKT2 signaling axis.
Prostate tumor RON receptor signaling mediates macrophage recruitment to drive androgen deprivation therapy resistance through Gas6-mediated Axl and RON signaling. [2023]Androgen deprivation therapy (ADT), or chemical castration, is the first-line therapy for prostate cancer; however, resistance leaves few treatment options. Prostatic tumor-associated macrophages (TAMs) have been shown to promote prostate cancer growth and are abundant in castration-resistant prostate cancer (CRPC), suggesting a role in promoting CRPC. We recently showed a tumor cell-intrinsic mechanism by which RON promotes CRPC. Given previous reports that RON alters prostate cancer cell chemokine production and RON-overexpressing tumors alter macrophage function, we hypothesized that a macrophage-dependent mechanism regulated by tumor cell intrinsic RON also promotes CRPC.
ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. [2023]The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.